Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin's lymphomas among relatives of patients with chronic lymphocytic leukemia

Abstract

BackgroundPrevious studies have shown increased familial risk for chronic lymphocytic leukemia. In the most comprehensive study to date, we evaluated risk of chronic lymphocytic leukemia and lymphoproliferative disorders among first-degree relatives of chronic lymphocytic leukemia cases compared to first-degree relatives of controls. Design and MethodsPopulation-based registry data from Sweden were used to evaluate outcomes in 26,947 first-degree relatives of 9,717 chronic lymphocytic leukemia patients (diagnosed 1958-2004) compared with 107,223 first-degree relatives of 38,159 matched controls. Using a marginal survival model, we calculated relative risks (RR) and 95% confidence intervals as measures of familial aggregation. ResultsCompared to relatives of controls, relatives of chronic lymphocytic leukemia patients had an increased risk for chronic lymphocytic leukemia (RR=8.5, 6.1-11.7) and other nonHodgkin's lymphomas (NHLs) (RR=1.9, 1.5-2.3). Evaluating NHL subtypes, we found a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. No excesses of aggressive B-cell or T-cell lymphomas were found. There was no statistical excess of Hodgkin's lymphoma, multiple myeloma, or the precursor condition, monoclonal gammopathy of undetermined significance, among chronic lymphocytic leukemia relatives. ConclusionsThese familial aggregations are striking and provide novel clues to research designed to uncover early pathogenetic mechanisms in chronic lymphocytic leukemia including studies to identify germ line susceptibility genes. However, clinicians should counsel their chronic lymphocytic leukemia patients emphasizing that because the baseline population risks are low, the absolute risk for a first-degree relative to develop chronic lymphocytic leukemia or another indolent lymphoma is low. At this time, an increased medical surveillance of first-degree relatives of chronic lymphocytic leukemia patients has no role outside research studies.

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

“…For prostate cancer, the best-fitting estimate of the genetic correlation between aggressive and nonaggressive disease was at the upper boundary (ρ = 1, SE = 0.25), indicating a * Comparison of first-degree familial relative risk (95% CI) measured by our genome-wide association study (last column) with estimates of familial relative risk from the three largest family studies. Prior estimates are from (1,6,10), except for CLL (31), DLBCL (32), glioma (sibling) (33), pancreas (34), and esophagus (3). CI = confidence interval; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; ER = estrogen receptor; FRR = family relative risk; GWAS = genome-wide association study.…”

Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies

“…3 Furthermore, we found significantly increased risk for NHL, including LPL/WM, and hairy cell leukemia. 15 However, there was no excess of HL, MM or MGUS (Table 1). These studies support the role of germ-line genes underlying risk of CLL and perhaps related malignancies.…”

“…11 We have evaluated the familial risk of CLL in two studies. 15,19 Recently, a study including almost 10,000 CLL patients and their close to 27,000 first-degree relatives showed that first degree relatives of CLL patients had an 8.5-fold increased risk for CLL. 15 This is similar to that observed in a registry study in Utah.…”

“…15,19 Recently, a study including almost 10,000 CLL patients and their close to 27,000 first-degree relatives showed that first degree relatives of CLL patients had an 8.5-fold increased risk for CLL. 15 This is similar to that observed in a registry study in Utah. 3 Furthermore, we found significantly increased risk for NHL, including LPL/WM, and hairy cell leukemia.…”

The molecular basis of familial chronic lymphocytic leukemia

“…11 This study was based on an analysis of 9,717 CLL cases and 38,159 controls ascertained through the Swedish Cancer Registry. Findings underscored CLL being characterized by a high familial relative risk (RR) -the RR of CLL in first-degree relatives of cases in this study was seen to be increased 8.5-fold.…”